1, 5-dialkyl tetrazoles and preparation thereof



Patented May 9, 1950 1,5-DIALKYL TETRAZOLES AND PREPARATION THEREOF Edward K. Harvill, Orange, and Robert M. Herbst, Short Hills, N. J assignors to E. Bilhuber, Inc., Orange, N. J., a corporation of New Jersey No Drawing. Application June 12, 1946, Serial No. 676,344

7 Claims.

This invention pertains to new and useful tetrazole compounds having valuable therapeutic properties therein, and to their preparation.

The new compounds of our invention comprise the 1,5 substituted, dialkyl tetrazoles of the general formula:

wherein R1 and R2 are aliphatic alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc., or cycloalkyl groups, such as cyclohexyl, cyclopentyl, etc.; and, more specifically, wherein one of the substituents R1 or R2 is pref erably an alkyl group of low order, such as methyl or ethyl, while the remainin substituent is an alkyl group of higher order, such as propyl, butyl, isopropyl, isobutyl, cyclohexyl, etc.

We have discovered, in accordance with an important aspect of our invention, that the 1,5 dialkyl tetrazoles of the character aforesaid are valuable therapeutic agents having marked pharmacological effects on the central nervous system, which vary in character and degree with the magnitudes and character of the alkyl substituents R1 and R2, and especially with the relative magnitudes of these substituents and their relative locations on the tetrazole ring.

Thus, we have discovered that whereas the parent compound, tetrazole, is substantially devoid of pharmacological action even when administered in large doses, the simplest of the 1,5 dialky] tetrazoles, viz., 1,5 dimethyl tetrazole, is very mildly sedative in its action. Also that if the substituent R1 attached to the nitrogen atom is kept relatively small, for example, methyl or ethyl, while the substituent R2 attached to the carbon atom is increased to a higher order, for example, propyl, butyl, etc., the sedative or depressant action of the compound increases markedly in intensity, assuming a maximum intensity when the R2 alkyl substituent is of the order of butyl, amyl or cyclohexyl. On the other hand, if the relative magnitudes of the substituents R1 and R2 are increased in the reverse order, that is to say, if the substituent R2 attached to the carbon atom remains small, i. e., methyl or ethyl, while the remaining substituent R1 attached to the nitrogen atom, is increased to a higher order, for example, propyl, butyl, etc., the pharmacological action of the compound changes from sedative or depressant in character to that of a stimulant, in which the stimulant action increases in intensity with the magnitude of the R1 substituent until a maximum stimulating action is obtained when R1 is of the order of isobutyl or cyclohexyl.

Thus, the invention provides a series of basically similar, 1,5 alkyl substituted, tetrazole compounds, the pharmacological efiects of which vary gradually in one direction from mildly sedative to intensely sedative or depressant in action, and which vary gradually in the opposite direction from mildly stimulating to intensely stimulating in action for a given dosage. These new compounds are characterized not only by a high level of potency as central nervous and respiratory stimulants or depressants, but are further characterized by unusually prolonged action thereof.

It is to be emphasized that it is the relative magnitudes of the substituents R1 and R2 on which the intensity of the depressant or stimulant activity depends. For example, the highly active stimulant, l-isobutyl-S-methyl tetrazole is almost completely inactivated by replacing the methyl group with an isobutyl group. Similarly, the extremely active 1-cyclohexyl-5-methyl tetrazole undergoes a decrease in potency when the methyl group is replaced by an ethyl group, and a substantially complete loss of activity when the methyl group is replaced by isobutyl or cyclohexyl. That is to say, if the substituents R1 and R2 are of the same order of magnitude, for example, both are butyl, isobutyl, cyclohexyl, etc., the therapeutic action of the resulting compound becomes substantially nil.

For a given number of carbon atoms in the alkyl substituents for R1 or R2, the branched chain groups, such as isopropyl, isobutyl, cyclohexyl, etc., impart to the resulting compound a more potent stimulant or depressant action than do the straight chain alkyl groups, such as propyl, butyl, etc. The substitution of aromatic groups, such as phenyl, for alkyl groups in R1 or R2 markedly decreases the potency of the compound, which is thereby rendered only mildly stimulating or depressant in action.

The new compounds of the invention may be prepared from appropriate monosubstituted acid amides of the general formula, R1NHCOR2, where R1 and R2 are aliphatic alkyl and cyclo-alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl and cyclopentyl.

In accordance with the invention, such amides are treated, in an indifferent or inert organic solvent, with phosphorus pentachloride, in connection with which we have found it be of the utmost importance for the successful synthesis of these new tetrazoles to keep the temperature of the reaction mixture below 50 C. At higher temperatures monosubstituted acid amides in which a hydrogen atom is present on the alphacarhon atom of the acidic portion, tend to halogenate on this alpha-carbon atom on treatment with phosphorus halides. These halogenated compounds are highly reactive and tend to condense and eliminate hydrogen chloride to form complex products at temperatures above 50 C.

At temperatures below '50" 0. treatment of the acid amide with phosphorus pentachloride favors the formation of the imido-chloride which without isolation on further treatment with hydrazoic acid or sodium azide leads to the production of the desired tetrazole.

The following examples are illustrative:

EXAMPLE. I

1 -cyclohea:yl-5-ethyl tctmaole To a cooled solution of 80 grams of N-cyclohexyl propionamide in 500 cc. of anhydrous ether, 106 grams of phosphorus pentachloride was-added portion-wise. The ether was removed from .a solid mass .of crystals under reduced pressure .by warming .the reaction mixture .to 419 $3. The residue .was treated with 500' cc. of hengene containing grams ,of .hydrazoic acid and the mixture allowed to stand .at room temperature for fifteen hours. The solution was then refluxed until hydrogen chloride evolution had ceased and the solvent was removed under reduced pressure.

solution .72 grams of lcyclohexyl-d-ethyl tetra- ,zole .was collected ,byfiltration, M. P. 111.-1l3

C. Recrystallization -from Water gave a white crystalline product,jM. P. 112-1125 C.

EXAMPLEI 1 -eyclohemyZ-5 -meth yl tctraaole To asolution of 160 grams of N-cyclohexylacetamide in 500 cc. of benzene, .147 grams of phosphorus pentachloride was added in small portions. The solution was cooled to keep the temperature below C. and moderate the vigorous reaction. To the cooled solution, 34 grams of 'hydrazoic acid in benzene was addedand after one hour the solution was refluxed, until hydrogen chloride evolution had ceased. The solvent was removed under reduced pressure and the residue was refluxed in water. From the cooled solution, l-cyclohexyl-5-methyl tetrazole separated as light yellow needles weighing '79 grams after drying. After .recrystallizing twice from water, grams of white crystalline product, melting at 124-1245 .C., was obtained.

-;By application of the methods disclosedin the foregoing examples to the appropriate monosubsti-tuted acid amides, the following 1,5-dialkyl tetrazoles have beenprepared:

Analysis Per Cent N Compound sg Calculated Fqlmd 1,5-.Dichlohexyl tetrazole 179. 5-180 23. 93 23. 88 1,5-Diisobutyl tetrazole 30. 77 30. 42 l-Ethyl-5-cyclohexyl tetrazole- 84-86 31. 11 '31. 24 l-Cyclohexyl--isohutyl tetrazo 78. 5:79 26. 92 26. 91 l-Cyclohexyl-5-ethyl tetrazole. 112-112. 5 31. 11 31. 14 l-Methyl-5-cyclohexyl tetrazole 97-98 33. 73 r 33. 74 l-lsobutyl-5-oyclohexyl vtetrazole 81-82 26. 92 26. 74 1-Oyclohexyl-5-methyl tetrazole 124-124 5 33. 73 33. 84 1'Oyclohcxyl-5-propyl tetrazole. 79-80 28.87 28. .91 l-Cyclohexyl -5-isopropyl tetrazole--- 85-86 28. 8 .28. l-Cyclohexyl-5-n-butyl tetra'zole. 43. 5-45. 0 26.92 27. 09 ,1-Cyolopentyl-5-methyl tetrazole 62-62. 5 36.60 36. 84 1-Hexahydrobenzyl-5-methyl tet- 87-88 31.11 31.26

razoie.

1-Isobutyl-5-methyl tetrazole. 45-455 40 O0 39. 70

I corneas/s an. Hg).

The residue was refluxed with 4 aqueous sodium hydroxide and from the cooled We-Q im 1. The therapeutically active ,tetrazole compound of the general formula:

wherein one of the radicals R1 and R2 is selected from the group consisting of methyl and ethyl,

and the remaining radical is selected from the group consisting of, saturated,

wherein R2 is selected from the group consisting of methyl and ethyl, and-R1 is selected from the group consisting of saturated, straight and branched chain alkyl radicals of threeand iour carbon atoms, and cycloalkyl radicals of five andsix carbon atoms.

4. The therapeutically active compound *l-eyclohexyl-fi-methyl tetrazole.

5. The therapeutically active compound l-cyclo'hexyl-5-ethyl tetrazole.

6. The therapeutically active compound l-isobutyI-E-methyl :tetrazole.

7. The method of preparing *tetrazole compounds of the general formula? wherein R1 and R2 are alkyl radicals, which com,- prises: reacting amono substituted acid amide of the general formul R1NHCOR2, wit-l1 phosphorus pentachloride in an inert organicsolvent in the absence of a basic catalyst at a temperature below 50 (3., and subsequent treatment, without isolation of the intermediates, with a member selected from the group consisting of hydrazoic acid and sodium azide.

EDWARD K. HARy pL. ROBERT nEaBs'r.

REFERENCES CITED The following references are of recqr din the file of this patent:

UNITED STATES PATENTS Name Date .Scheuing Jan-9, 1934 OTHER REFERENCES Chemical Abstract, vol. 40, page 6656 citing Gross et al., Jr., Pharmacology and Experimental Therapeutics, vol. 87, vpp. 299-305 (1946).

Number 

1. THE THERAPEUTICALLY ACTIVE TETRAZOLE COMPOUND OF THE GENERAL FORMULA: 